In Vitro Generation of Luminal Vasculature in Liver Organoids: From Basic Vascular Biology to Vascularized Hepatic Organoids

Abstract

Liver organoids have gained much attention in recent years for their potential applications to liver disease modeling and pharmacologic drug screening. Liver organoids produced in vitro reflect some aspects of the in vivo physiological and pathological conditions of the liver. However, the generation of liver organoids with perfusable luminal vasculature remains a major challenge, hindering precise and effective modeling of liver diseases. Furthermore, vascularization is required for large organoids or assembloids to closely mimic the complexity of tissue architecture without cell death in the core region. A few studies have successfully generated liver organoids with endothelial cell networks, but most of these vascular networks produced luminal structures after being transplanted into tissues of host animals. Therefore, formation of luminal vasculature is an unmet need to overcome the limitation of liver organoids as an in vitro model investigating different acute and chronic liver diseases. Here, we provide an overview of the unique features of hepatic vasculature under pathophysiological conditions and summarize the biochemical and biophysical cues that drive vasculogenesis and angiogenesis in vitro. We also highlight recent progress in generating vascularized liver organoids in vitro and discuss potential strategies that may enable the generation of perfusable luminal vasculature in liver organoids.

Guidelines for Manufacturing and Application of Organoids: Liver

“…The liver’s intricate architecture comprises liver lobules and essential vascular networks that support its functionality. Recent progress in generating matured liver organoids, characterized by multi-lineage incorporation and vascularization, has significantly advanced the replication of the liver’s structural complexity and intercellular communication, enhancing its overall functionality ( 17 , 18 ). Notably, the structural integrity within the functional luminal vasculature within these organoids closely resembles in vivo conditions, facilitating more accurate simulations of the drug, oxygen, and nutrient transports ( 17 ).…”

“…Recent progress in generating matured liver organoids, characterized by multi-lineage incorporation and vascularization, has significantly advanced the replication of the liver’s structural complexity and intercellular communication, enhancing its overall functionality ( 17 , 18 ). Notably, the structural integrity within the functional luminal vasculature within these organoids closely resembles in vivo conditions, facilitating more accurate simulations of the drug, oxygen, and nutrient transports ( 17 ). This fidelity to physiological conditions holds promise for improving predictions in toxicity testing and therapeutic efficacy assessments.…”